具抑制P糖蛋白作用的自组装环糊精修饰载体的构建及其促药物口服吸收研究

It is well known that P-glycoprotein (P-gp) located in intestinal epithelium cells often leads to poor oral bioavailability of those drugs as P-gp substrates. With the aim?to overcome this problem, this project will design and synthesize in a controlled manner a series of amphiphilic β-cyclodextrin (β-CD) modified polymers with the capability to inhibit P-gp action. By testing on MDCK-MDR1 cells with high expression of P-gp, the impact of polymer on P-gp activity and its action mechanism will be fully investigated by various molecular biologic methods. Based on these experiments, we will choose some P-gp substrates with poor bioavailability as model drugs and construct drug-loaded self-assembles using some promising polymeric carriers. Then with MDCK-MDR1 monolayer membrane model, the trans-membrane tests will be explored to find out if the polymer can improve drug membrane transport and how it works. Followed by pharmacokinetics and pharmacodynamics studies, some optimized polymers as drug carriers will be finally obtained. The relationship among polymer chemical structure, polymer physicochemical properties and the assistance to drug absorption is expected to be clarified. And the effect of CD modification is emphasized. This project will not also prepare some polymeric carriers but also contribute some new ideas and experimental evidence to how to improve oral bioavailability via nano-scaled self-assembled polymers.

针对肠上皮细胞P糖蛋白（P-gp）分布导致其底物类药物口服生物利用度低的问题，拟设计并可控合成系列具有抑制P-gp作用的环糊精修饰的两亲性聚合物；以P-gp高表达的MDCK-MDR1细胞为模型，采用多种分子生物学实验手段，阐明聚合物抑制P-gp的作用机制及构效关系；在此基础上，选择若干P-gp底物为模型药物，构建载药纳米自组装体；研究其生物膜转运机制，揭示载体化学结构、载体性质与药物跨膜转运的内在关系和规律，特别是环糊精修饰的作用，确定载体结构中的关键影响因素；并进一步通过药动及药效学评价，筛选优化载体结构，最终获得能够高效装载药物并促进药物跨膜转运的新型环糊精修饰药物载体及纳米给药系统，为提高药物口服生物利用度提供新思路以及充分的实验依据。

如何提高药物口服生物利用度是当前药剂学领域迫切亟待解决的重要问题之一，而P糖蛋白（P-gp）在肠道的分布是导致药物吸收差的主要原因。针对这一问题，我们设计和合成了具有P-gp抑制作用的两亲性环糊精修饰聚合物，阐明了载体对P-gp抑制作用及促进生物膜转运的作用机制及构效关系，获得具有明显促进P-gp底物类药物口服生物利用度的载体及纳米自组装给药系统。研究成果以通讯作者发表SCI论文10篇，总IF为45.411；邀请会议报告2次；培养博士生4名、硕士生1名和博士后1名；新当选中国医药生物技术协会纳米生物技术分会常务委员。本项目按计划完成，达到研究目标，所获得的实验结果和理论经验对推动功能型药用辅料和创新制剂的深入研发具有重要意义。